Projectdetails

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Molecular mechanisms involved in BCR-ABL/BMI1 induced self-renewal of leukemic stem cells

Keywords:
hematopoiesis leukemic stem cells self-renewal human hematopoietic stem cells

Researchers:
prof. dr. J.J. Schuringa

Type of project:
Stage Wetenschap / Research project

Nature of the research:
Stage Wetenschap / Research project

Fields of study:
oncology haematology

Background / introduction
Acute myeloid leukemia (AML) consists of a heterogeneous population of malignant cells that appears to be hierarchically structured, just as the normal hematopoietic system. Within this heterogeneous population of AML cells only a limited number of primitive cells can self-renew, termed leukemic stem cells. These leukemic stem cells can engraft NOD-SCID/NSG mice, are relatively insensitive to chemotherapy, and are most likely the main cause of relapse of disease. In order to improve treatment strategies, we need to obtain more insight into the biology of these leukemic stem cells
Research question / problem definition
Recent studies in our lab have shown that co-expression of BCR-ABL and the polycomb member BMI1 in normal human hematopoietic stem cells is sufficient to induce leukemia upon transplantation into mice. Both myeloid as well as lymphoid transformation could be achieved, depending on cell-extrinsic cues. This model now puts us in a unique position to further characterize the mechanisms that underlie the development of leukemia in detail.
Workplan
-Recent genome-wide gene expression profiling identified a series of BCR-ABL/BMI1 target genes that will be analyzed in our human leukemia models as well as in primary patient samples
-We would like to identify whether differences exist between the “cell of origin” (from which the leukemia arises) versus the “cell of maintenance” (that continues to drive leukemic growth)
-We would like to identify whether different clones give rise to myeloid versus lymphoid leukemias, and whether certain leukemic clones can switch lineage by changing their extrinsic environment.
References
-Rizo A, Horton SJ, Olthof S, Dontje B, Ausema A, van Os R, van den Boom V, Vellenga E, de Haan G, Schuringa JJ. BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells. Blood. 2010 Nov 25;116(22):4621-30.
-Schuringa JJ and Vellenga E. (2010): Role of polycomb group gene BMI1 in normal and leukemic human hematopoietic stem/progenitor cells. Current Opinion in Hematology 17:294-9.
-Rizo A, Olthof S, Vellenga E, de Haan G, and Schuringa JJ. (2008). Downmodulation of BMI1 impairs long-term self-renewal of normal human as well as leukemic CD34+ cells. Blood, 114:1498-505.
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